The present invention relates to radiation sterilization and more particularly to determining a minimal, yet effective, radiation dosage for sterilization.
Dose setting Methods 1 and 2, used for the validation establishment of a radiation sterilization dose, were developed in the early 1980's. At that time, 2.5 megarads (25 kGy) was viewed as a generally acceptable dose for the sterilization of medical devices. It was recognized, however, that many medical devices would have a sterility assurance level (SAL) of 10−6 at lower doses and some would require a dose greater than 25 kGy to attain this SAL. Important characteristics of the medical devices used in the developmental work for Methods 1 and 2 were their manufacture in minimally controlled environments, resulting in relatively higher levels and diversity of types of bioburden, and materials of construction that were relatively unaffected by radiation doses of 25 to 75 kGy.
Many health care products that are currently in development differ significantly from those produced in the early 1980's in that they have one or more bioactive components that are relatively sensitive to radiation damage and they are manufactured in a highly controlled environment which limits the numbers and types of contaminating microorganisms. Often, some or all of the components of these health care products are sterilized prior to introduction into the manufacturing process.
The key underlying principle of Methods 1 and 2 (see ISO 11137-2, 2006) is the use of direct testing of the radiation response of the product bioburden as part of the determination of a dose to attain an SAL of 10−6. With both methods, a test is performed where 100 product items are irradiated and a test of sterility is performed at a dose that is expected to result in ˜1 nonsterile item (10−2 SAL) out of the 100 items tested.
Method 2B is indicated for “low and consistent bioburden” but these qualitative terms are not strictly defined. With this method, no determination of product bioburden level is made and the radiation dose used for the 100 product items is estimated by the performance of an “incremental dose experiment” (IDE); this method uses an IDE with the following target dose values: 1, 2, 3, 4, 5, 6, 7, and 8 kGy. Twenty product items are irradiated at each of these doses and subjected to a test of sterility. The purpose of the IDE is to identify the “first-fraction-positive” (FFP) dose, the first dose where at least one product item is found to be sterile and the remaining items nonsterile (such as 19/20 nonsterile).
The lowest dose in the IDE whose outcome is 0+/20 is an estimate of the dose that will yield a 10−2 SAL. One hundred product items are irradiated at this dose; this test is termed the “verification dose experiment” (VDE). If 0, 1, or 2 positive tests of sterility are observed in the VDE, the delivered dose is termed the “First-No-Positive” (FNP) dose. The determination of the FFP and FNP doses allows, in Method 2, for the calculation of a factor, termed “DS”, that is used to derive a 10−6 sterilization dose from the experimentally determined 10−2 SAL dose.
The difficulty in applying Method 2B for current products with low average bioburden that are manufactured in highly-controlled environments is the manner in which the DS value is calculated. The use of the calculation “DS=1.6+[0.2(FNP−FFP)]” effectively puts a floor on the DS value equal to 1.8 kGy which yields a minimum sterilization dose of 8.2 kGy [sterilization dose=10−2 dose+4(DS)=1.0+4(1.8)=8.2; FNP=1.0 kGy]. A sterilization dose of 8.2 kGy is overly conservative, for example, for a product with a bioburden of 1.0 composed of microorganisms that are relatively sensitive to radiation. The present invention overcomes the limitations of the methods in the current standards in determining an effective dose for radiation sensitive materials having low bioburdens.